LZTS1 (leucine zipper, putative tumor suppressor 1)
2012-06-01 Andrea Vecchione , Luca Lavra , Carlo M Croce AffiliationDNA/RNA
Note
NC_000008.10: 20103676 - 20112803 bp (Entrez-Gene).
Genomic structure of the human LZTS1 gene.
Description
According to Entrez-Gene, LZTS1 gene extends over 9 kb (9128 bases) and consists of 3 exons.
Transcription
mRNA size: 5459 bp (NM_021020.2); open reading frame: 1791 bp (NP_066300.1).
LZTS1 mRNA is highly expressed in testis, prostate, spleen, thymus, ovary and brain. It has been detected at lower levels in heart, placenta, small intestine, colon, liver, kidney, skeletal muscle and pancreas. LZTS1 gene is not expressed in primary tumors from breast and prostate and in different cancer cell lines (Ishii et al., 1999).
LZTS1 mRNA is highly expressed in testis, prostate, spleen, thymus, ovary and brain. It has been detected at lower levels in heart, placenta, small intestine, colon, liver, kidney, skeletal muscle and pancreas. LZTS1 gene is not expressed in primary tumors from breast and prostate and in different cancer cell lines (Ishii et al., 1999).
Pseudogene
No LZTS1 pseudogenes have been reported.
Proteins
Schematic representation of LZTS1 protein. The leucine residues position of leucine-zipper motifs are indicated by the gray bars.
Description
LZTS1 gene encodes a 596-aa protein of 67 kDa. The protein contains two leucine-zipper motifs, multiple potential phosphorylation sites for different kinases (e.g. PKA, CDC2 and PKC) and a domain with 32% identity to the DNA binding domain of the cAMP-responsive transcription factor Atf5. LZTS1 lacks the DNA recognition domain usually found in transcription factors carrying a leucine-zipper motive (Ishii et al., 1999; Ishii et al., 2001; Vecchione et al., 2007b).
Expression
LZTS1 is ubiquitously expressed in all normal human tissues. LZTS1 protein expression is lost or reduced in different primary tumors.
Localisation
Main sub-cellular localizations: plasma membrane and cytoplasm.
Additional localizations: nucleoli (observed in U2-OS cells) and Golgi apparatus (observed in A-431 cells) (Barbe et al., 2008).
Additional localizations: nucleoli (observed in U2-OS cells) and Golgi apparatus (observed in A-431 cells) (Barbe et al., 2008).
Function
Cell cycle regulation. It has been demonstrated that Lzts1-/- mouse embryonic fibroblasts (MEF) have a faster M phase, associated with a lower cyclin B1/Cdk1 activity. During prophase the interaction between LZTS1 and Cdc25C, a phosphatase implicated in regulation of Cdk1 activity, allows the expression of high levels of Cdc25C and enhances its activity, resulting in normal progression from prophase to metaphase. In Lzts1 deficient cells during prophase Cdc25C is rapidly ubiquitinated and degraded, thus determining a lower activity of the cyclin B1/Cdk1 complex. This results in a faster cellular progression through prophase and prometaphase and, frequently, in chromosome missegregation (Vecchione et al., 2007b).
Homology
The LZTS1 gene is conserved in the organisms listed below:
- Pan troglodytes (LZTS1) (Gene ID: 464034)
- Macaca mulatta (LZTS1) (Gene ID: 705724)
- Mus musculus (Lzts1) (Gene ID: 211134)
- Rattus norvegicus (Lzts1) (Gene ID: 266711)
- Bos taurus (LZTS1) (Gene ID: 539634)
- Equus caballus (LZTS1) (Gene ID: 100053630)
- Canis lupus familiaris (LZTS1) (Gene ID: 486136)
- Monodelphis domestica (LZTS1) (Gene ID: 100030407)
- Ornithorhynchus anatinus (LZTS1) (Gene ID: 100073437)
- Gallus gallus (LZTS1) (Gene ID: 431331)
- Danio rerio (si:dkey-63d15.13) (Gene ID: 569281).
- Pan troglodytes (LZTS1) (Gene ID: 464034)
- Macaca mulatta (LZTS1) (Gene ID: 705724)
- Mus musculus (Lzts1) (Gene ID: 211134)
- Rattus norvegicus (Lzts1) (Gene ID: 266711)
- Bos taurus (LZTS1) (Gene ID: 539634)
- Equus caballus (LZTS1) (Gene ID: 100053630)
- Canis lupus familiaris (LZTS1) (Gene ID: 486136)
- Monodelphis domestica (LZTS1) (Gene ID: 100030407)
- Ornithorhynchus anatinus (LZTS1) (Gene ID: 100073437)
- Gallus gallus (LZTS1) (Gene ID: 431331)
- Danio rerio (si:dkey-63d15.13) (Gene ID: 569281).
Mutations
Note
Sequence analysis of LZTS1 ORF, performed in different type of cancers revealed the presence of the somatic point mutations listed hereinafter (Vecchione et al., 2001; Knowles et al., 2005):
- S29P: (TCC->CCC) reported in a primary esophageal tumor
- K119E: (AAG->GAG) reported in a primary esophageal tumor
- Q501Stop: (CAG->TAG) reported in PC3 (prostate cancer cell line)
- H17R: (CAC->CGC) reported in a diffuse-type gastric carcinoma
- L113P: (CTA->CCA) reported in a bladder tumor sample
- G374S: (GGC->AGC) reported in A1698 (bladder cancer cell line)
- L475V: (CTG->GTG) reported in SCaBER (bladder cancer cell line).
- S29P: (TCC->CCC) reported in a primary esophageal tumor
- K119E: (AAG->GAG) reported in a primary esophageal tumor
- Q501Stop: (CAG->TAG) reported in PC3 (prostate cancer cell line)
- H17R: (CAC->CGC) reported in a diffuse-type gastric carcinoma
- L113P: (CTA->CCA) reported in a bladder tumor sample
- G374S: (GGC->AGC) reported in A1698 (bladder cancer cell line)
- L475V: (CTG->GTG) reported in SCaBER (bladder cancer cell line).
Internally truncated transcripts described in different cancers (Ishii et al., 1999):
- Frameshift deletion 1546-1542 (exons affected: 1,2,3) reported in esophagus cancer
- In-frame deletion 558-1715 (exons affected: 2,3) reported in esophagus cancer
- In-frame deletion 1366-1641 (exon affected: 3) reported in prostate cancer
- In-frame deletion 1402-1578 (exon affected: 3) reported in esophagus and prostate cancer and in acute lymphoblastic leukemia
- In-frame deletion 1417-1515 (exon affected: 3) reported in melanoma
- In-frame deletion 1516-1584 (exon affected: 3) reported in melanoma.
A detailed DNA sequence analysis of LZTS1 gene performed in germline DNA extracted from a screening panel of sporadic and hereditary prostate cancers revealed the presence of 24 SNP. The four SNP listed below have a statistically significant association with sporadic prostate cancer (Hawkins et al., 2002):
- A allele of WF101-010 (2812G → A)
- C allele of WF101-012 (2883T → C)
- C allele of WF101-031 (3329C → T)
- G allele of WF101-014 (4361C → T).
Implicated in
Entity name
Prostate cancer
Note
The DNA sequence analysis of LZTS1 performed on sporadic and hereditary prostate cancer (HPC) samples and unaffected controls revealed the presence of several SNPs associated with prostate cancer (Hawkins et al., 2002). Over-expression of LZTS1 cDNA modulates colony-forming efficiency and proliferation in different prostate cancer cell lines (Cabeza-Arvelaiz et al., 2001).
Entity name
Ovarian cancer
Note
An immunohistochemical analysis of LZTS1 protein expression performed in ovarian carcinomas tissue samples demonstrated that cytoplasmic staining for FEZ1 protein was absent or drastically reduced in 38% of cases (Califano et al., 2010). In addition, homozygous deletions at LZTS1 locus has been detected in advanced ovarian clear cell carcinomas (Kuo et al., 2010).
Entity name
Oral squamous cell carcinoma
Note
Reduced LZTS1 gene expression has been reported in 35% of oral squamous cell carcinoma (SSC) samples and in oral SSC-derived cell lines (Ono et al., 2003).
Entity name
Uveal melanoma
Note
A gene expression profiling performed on 53 primary uveal melanomas by array-based comparative genomic hybridization demonstrated that LZTS1 expression was reduced in rapidly metastasizing and metastatic uveal melanomas but not in slowly metastasizing and non metastasizing uveal melanomas.
Moreover overexpression of LZTS1 in metastasizing uveal melanoma-derived cells inhibited their motility and invasion (Onken et al., 2008).
Moreover overexpression of LZTS1 in metastasizing uveal melanoma-derived cells inhibited their motility and invasion (Onken et al., 2008).
Entity name
Lung carcinoma
Note
The immunohistochemical analysis of LZTS1 expression in 103 primary lung cancer specimens demonstrated absence or strong reduction in respectively in more that 42% of cases. A positive correlation between loss of LZTS1 and tumor grading, and between strong LZTS1 expression and mortality rate reduction was also observed (Nonaka et al., 2005). Moreover reduced LZTS1 expression was also detected in several lung cancer derived cell lines (Toyooka et al., 2002).
Entity name
Gastric carcinoma
Note
The immunohistochemical analysis of LZTS1 expression, performed in 88 gastric cancer specimens demonstrated that it is lost or significantly reduced in more than 44% of cases. In addition, DNA allelotyping analysis at the LZTS1 locus showed LOH and microsatellite instability respectively in 18% and 23,5% of cases (Vecchione et al., 2001).
Entity name
Breast carcinoma
Note
LZTS1 gene expression was reduced in breast primary tumors and breast cancer cell lines. The immunohistochemical analysis of LZTS1 expression demonstrated that LZTS1 was absent or down-regulated in primary breast carcinomas compared with normal breast. Moreover, reduced LZTS1 expression was significantly correlated with high histologic grade, lymph node metastasis, and poor prognosis. In addition, DNA methylation analysis demonstrated that LZTS1 loss of expression in breast tumors is correlated with gene methylation. Moreover, overexpression of LZTS1 in breast cancer cell lines inhibits cell proliferation, migration and invasion, and induces morphological and molecular changes characteristic of mesenchymal-to-epithelial transition (Chen et al., 2009; Wang et al., 2011).
Entity name
Bladder cancer
Note
LZTS1 protein expression is reduced in bladder tumor samples and bladder cancer derived cell lines. Reintroduction of LZTS1 expression in TCC derived cell line inhibited cell growth, altered cell cycle progression and suppressed subcutaneous tumor growth in nude mice. Several LZTS1 somatic point mutations have also been reported in bladder cancers tissues and cell lines (Vecchione et al., 2002; Knowles et al., 2005). Moreover, it has been demonstrated by treating heterozygous and nullizygous Lzts1 mice with a classical bladder carcinogen (N-butyl-N-(4-hydroxybutil) nitrosamine, BBN), that the loss of one or both Lzts1 alleles favored development of bladder cancer. These results demonstrated that LZTS1 could represent an important therapeutic target for bladder tumor treatment.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 18192690 | 2008 | Fez1/Lzts1-deficient mice are more susceptible to N-butyl-N-(4-hydroxybutil) nitrosamine (BBN) carcinogenesis. | Baffa R et al |
| 17873519 | 2007 | Take your "M" time. | Baldassarre G et al |
| 18029348 | 2008 | Toward a confocal subcellular atlas of the human proteome. | Barbe L et al |
| 11464283 | 2001 | Functional identification of LZTS1 as a candidate prostate tumor suppressor gene on human chromosome 8p22. | Cabeza-Arvelaiz Y et al |
| 19885841 | 2010 | FEZ1/LZTS1 protein expression in ovarian cancer. | Califano D et al |
| 18686028 | 2009 | Down-regulation of tumor suppressor gene FEZ1/LZTS1 in breast carcinoma involves promoter methylation and associates with metastasis. | Chen L et al |
| 12377406 | 2002 | Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk. | Hawkins GA et al |
| 10097140 | 1999 | The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors. | Ishii H et al |
| 11504921 | 2001 | FEZ1/LZTS1 gene at 8p22 suppresses cancer cell growth and regulates mitosis. | Ishii H et al |
| 15922864 | 2005 | Mutation analysis of the 8p candidate tumour suppressor genes DBC2 (RHOBTB2) and LZTS1 in bladder cancer. | Knowles MA et al |
| 20233889 | 2010 | DNA copy numbers profiles in affinity-purified ovarian clear cell carcinoma. | Kuo KT et al |
| 15735004 | 2005 | Reduced FEZ1/LZTS1 expression and outcome prediction in lung cancer. | Nonaka D et al |
| 18559591 | 2008 | A metastasis modifier locus on human chromosome 8p in uveal melanoma identified by integrative genomic analysis. | Onken MD et al |
| 12851677 | 2003 | Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas. | Ono K et al |
| 12114433 | 2002 | Differential expression of FEZ1/LZTS1 gene in lung cancers and their cell cultures. | Toyooka S et al |
| 17718912 | 2007 | Fez1/Lzts1 a new mitotic regulator implicated in cancer development. | Vecchione A et al |
| 21419475 | 2011 | Down-regulation of leucine zipper putative tumor suppressor 1 is associated with poor prognosis, increased cell motility and invasion, and epithelial-to-mesenchymal transition characteristics in human breast carcinoma. | Wang XX et al |
Other Information
Locus ID:
NCBI: 11178
MIM: 606551
HGNC: 13861
Ensembl: ENSG00000061337
Variants:
dbSNP: 11178
ClinVar: 11178
TCGA: ENSG00000061337
COSMIC: LZTS1
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000061337 | ENST00000265801 | Q9Y250 |
| ENSG00000061337 | ENST00000381569 | Q9Y250 |
| ENSG00000061337 | ENST00000522290 | Q9Y250 |
| ENSG00000061337 | ENST00000616228 | Q9Y250 |
Expression (GTEx)
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 25667121 | 2015 | The tumor-suppressor gene LZTS1 suppresses colorectal cancer proliferation through inhibition of the AKT-mTOR signaling pathway. | 17 |
| 25813822 | 2015 | Loss of Leucine Zipper Putative Tumor Suppressor 1 (LZTS1) Expression Contributes to Lymph Node Metastasis of Breast Invasive Micropapillary Carcinoma. | 11 |
| 25938461 | 2015 | MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma. | 16 |
| 26504261 | 2015 | Ehlers-Danlos Syndrome, Hypermobility Type, Is Linked to Chromosome 8p22-8p21.1 in an Extended Belgian Family. | 10 |
| 26653561 | 2015 | The tumor-suppressor gene LZTS1 suppresses hepatocellular carcinoma proliferation by impairing PI3K/Akt pathway. | 7 |
| 25667121 | 2015 | The tumor-suppressor gene LZTS1 suppresses colorectal cancer proliferation through inhibition of the AKT-mTOR signaling pathway. | 17 |
| 25813822 | 2015 | Loss of Leucine Zipper Putative Tumor Suppressor 1 (LZTS1) Expression Contributes to Lymph Node Metastasis of Breast Invasive Micropapillary Carcinoma. | 11 |
| 25938461 | 2015 | MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma. | 16 |
| 26504261 | 2015 | Ehlers-Danlos Syndrome, Hypermobility Type, Is Linked to Chromosome 8p22-8p21.1 in an Extended Belgian Family. | 10 |
| 26653561 | 2015 | The tumor-suppressor gene LZTS1 suppresses hepatocellular carcinoma proliferation by impairing PI3K/Akt pathway. | 7 |
| 24448468 | 2014 | LZTS1 downregulation confers paclitaxel resistance and is associated with worse prognosis in breast cancer. | 14 |
| 24802407 | 2014 | miR-214 promotes the proliferation and invasion of osteosarcoma cells through direct suppression of LZTS1. | 22 |
| 24448468 | 2014 | LZTS1 downregulation confers paclitaxel resistance and is associated with worse prognosis in breast cancer. | 14 |
| 24802407 | 2014 | miR-214 promotes the proliferation and invasion of osteosarcoma cells through direct suppression of LZTS1. | 22 |
| 23695671 | 2013 | MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1. | 146 |
Citation
Andrea Vecchione ; Luca Lavra ; Carlo M Croce
LZTS1 (leucine zipper, putative tumor suppressor 1)
Atlas Genet Cytogenet Oncol Haematol. 2012-06-01
Online version: http://atlasgeneticsoncology.org/gene/367/lzts1-(leucine-zipper-putative-tumor-suppressor-1)
